Lymphohematopoietic graft-versus-host responses promote mixed chimerism in patients receiving intestinal transplantation
Jianing Fu, … , Tomoaki Kato, Megan Sykes
Jianing Fu, … , Tomoaki Kato, Megan Sykes
Published February 25, 2021
Citation Information: J Clin Invest. 2021;131(8):e141698. https://doi.org/10.1172/JCI141698.
View: Text | PDF
Research Article Immunology Transplantation

Lymphohematopoietic graft-versus-host responses promote mixed chimerism in patients receiving intestinal transplantation

Abstract

In humans receiving intestinal transplantation (ITx), long-term multilineage blood chimerism often develops. Donor T cell macrochimerism (≥4%) frequently occurs without graft-versus-host disease (GVHD) and is associated with reduced rejection. Here we demonstrate that patients with macrochimerism had high graft-versus-host (GvH) to host-versus-graft (HvG) T cell clonal ratios in their allografts. These GvH clones entered the circulation, where their peak levels were associated with declines in HvG clones early after transplant, suggesting that GvH reactions may contribute to chimerism and control HvG responses without causing GVHD. Consistently, donor-derived T cells, including GvH clones, and CD34+ hematopoietic stem and progenitor cells (HSPCs) were simultaneously detected in the recipients’ BM more than 100 days after transplant. Individual GvH clones appeared in ileal mucosa or PBMCs before detection in recipient BM, consistent with an intestinal mucosal origin, where donor GvH-reactive T cells expanded early upon entry of recipient APCs into the graft. These results, combined with cytotoxic single-cell transcriptional profiles of donor T cells in recipient BM, suggest that tissue-resident GvH-reactive donor T cells migrated into the recipient circulation and BM, where they destroyed recipient hematopoietic cells through cytolytic effector functions and promoted engraftment of graft-derived HSPCs that maintain chimerism. These mechanisms suggest an approach to achieving intestinal allograft tolerance.

Authors

Jianing Fu, Julien Zuber, Brittany Shonts, Aleksandar Obradovic, Zicheng Wang, Kristjana Frangaj, Wenzhao Meng, Aaron M. Rosenfeld, Elizabeth E. Waffarn, Peter Liou, Sai-ping Lau, Thomas M. Savage, Suxiao Yang, Kortney Rogers, Nichole M. Danzl, Shilpa Ravella, Prakash Satwani, Alina Iuga, Siu-hong Ho, Adam Griesemer, Yufeng Shen, Eline T. Luning Prak, Mercedes Martinez, Tomoaki Kato, Megan Sykes

×

Figure 6

BM-infiltrating donor T cells contain dominant clusters of cytotoxic effector T cells and undifferentiated/memory stem T cells.

Options: View larger image (or click on image) Download as PowerPoint
BM-infiltrating donor T cells contain dominant clusters of cytotoxic eff...
(A) Dominant DE genes by log2 fold change in major T cell clusters of each sample described in Figure 5B. FACS-sorted donor T cells were obtained from recipient BM from Pt18 POD357, Pt19 POD105, and Pt16’’ POD126. Clusters are annotated with major functional features and T cell subsets. Tscm: stem cell–like memory T cells; Tn: naive T cells; Tcm: central memory T cells. (B) GO term analysis using shared DE genes among Pt18_cluster 0/1/2/3, Pt19_cluster 0, and Pt16’’_cluster 1/3/4/6 (left panel) and among Pt18_cluster 4, Pt19_cluster 1, and Pt16’’_cluster 0 (right panel) are shown with up to 4 top nonredundant T cell relevant biological processes. P < 0.05 (–log10 P > 1.122) is considered to be statistically significant. Representative genes related to cytotoxicity and effector T cell functions are labeled with red and light blue, respectively. Genes related to undifferentiated/memory stem T cell subsets, including Tscm, Tn, and Tcm, are labeled with teal. (C) Normalized log fold changes in expression of subset-related transcription factor genes (TBX21, TCF7, LEF1), Tscm genes (TCF7, LEF1, SELL, CCR7), and cytotoxicity genes (GZMB, PRF1, GZMA, GNLY) for CD8 GvH (n = 8) and CD8 Tscm (n = 132) cells in BM-infiltrating donor T cells in Pt16’’ POD126. CD8 Tscm cells (n = 132) in cluster 0 of Pt16’’ expressed CD8A/CD8B but lacked CD4, TRDC, and Foxp3. Mann-Whitney U test was performed. ****P < 0.0001; ***P < 0.001; **P < 0.01.